Vascular endothelial growth factor (VEGF) is a proangiogenic factor that is secreted by tumor cells to stimulate endothelial cells to proliferate and form new blood vessels. Angiogenesis, which is the process by which new blood vessels are formed from the existing vasculature, is essential for the development and continuing growth of human tumors, and is necessary for the formation of metastases. Inhibiting angiogenesis is an important goal in the treatment of a variety of cancers, and therefore VEGF has become an important drug target for the prevention and treatment of these cancers. Drugs developed to inhibit VEGF target either VEGF itself, or one of the VEGF receptors.
Among the commonly used VEGF inhibitors in cancer therapy are bevacizumab (Avastin®), ranibizumab (Lucentis®), sunitinib (Sutent®), sorafenib (Nexavar®), axitinib, and pazopanib.
A side of effect of treatment with VEGF inhibitors is the presentation of dermatologic toxicities that can manifest on many areas of the body, and in particular, the hands and feet, as well as on the face, cheeks, and back of patients; toxicities also present on the nails and affect hair follicles are hair growth. The dermatologic toxicities can include hand-foot syndrome, acneiform rashes such as papulopustular rashes, as well as psoriasis, pruritus, paronychia, and changes in hair growth. Patients may also develop various other skin rashes, and problems relating to the eyelids and eyelashes. Hand and foot blisters are often associated with VEGF inhibitor treatment. Because hand and foot surfaces are under pressure from walking and other activity, the skin in these areas is more sensitive, and pressure points can develop to contribute to the blisters and erythema.
These dermatologic toxicities can begin to manifest soon after VEGF inhibitor treatment or up to several months following the end of treatment. In some circumstances, conditions such as psoriasis can develop after the papulopustular rash has resolved.
The severity of the toxicities can vary throughout treatment, and can depend on the specific VEGF inhibitor used, and can even resolve, temporarily, throughout the duration of treatment. Once treatment discontinues, however, these toxicities can disappear.
Patients often discontinue VEGF inhibitor treatment as a result of the side effects. Frequently, therefore, physicians lower the VEGF inhibitor dosage to decrease the scale of the side effects, and in many cases, treatment is delayed as a result.
Importantly, there is a positive correlation between the severity of the dermatologic toxicities and how effective an VEGF inhibitor is in treating a patient's cancer. Studies demonstrate this positive correlation between development of the rash or other skin eruption, and clinical outcomes, including the extent to which a patient's tumor shrinks Therefore, a means of preventing and/or treating side effects that might hinder the administration of VEGF inhibitors is crucial.
Many treatments to manage VEGF inhibitor side effects on the skin and related areas have been attempted, including the use of tetracycline, mild cleansers, hydrocortisone, clindamycin gel, and tacrolimus cream, as well as sunscreen and analgesics. These agents have proved largely unsuccessful in treating the toxic side effects of VEGF inhibitor treatment, and therefore there is a need for additional therapies that are efficacious in preventing and treating these unpleasant side effects.